1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one or Ibrutinibis an inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
Ibrutinib was approved by USFDA in 2013 and is marketed under the brand name IMBRUVICA®, is an important kinase inhibitor indicated for the treatment of patients with: Mantle cell lymphomas (MCL), who have received at least one prior therapy (1.1). Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. Further, it was approved for the treatment of Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy (1.2), Chronic lymphocytic leukemia with 17p deletion (1.3) and Waldenström's macroglobulinemia (WM)
Ibrutinib was chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (I).
Ibrutinib is a white to off-white solid substance with the empirical formula C25H24N6O2 and a molecular weight of 440.5. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.
Ibrutinib is generically disclosed in U.S. Pat. No. 7,351,834, and specifically disclosed in U.S. Pat. No. 8,637,553. These patents disclose a process for the preparation of lbrutinib starting from 4-Aminopyrazolo[3,4-d]pyrimidine. The process is as demonstrated in Scheme-I:

US 2013/0338172 disclose crystalline Form A, Form B, Faun C, Form D (MIBK Solvate), Form E (Toluene Solvate) and Form F (MeOH solvate) of Ibrutinib. This patent application further discloses that Ibrutinib prepared as outlined in U.S. Pat. No. 7,514,444 results in amorphous form. (Anhydrous)
EP 2543375 discloses different processes for the preparation of inhibitors of Bruton's Tyrosine Kinase. The processes disclosed in EP '375 are as disclosed below:





WO 2015145415 discloses crystalline Form III (1,4-dioxane solvate), Form IV(1,2-dimethoxyethane solvate), Form V (Methanol solvate), Form VI (Anhydrous), Form VII (Anisole solvate), Form VIII and Form IX (Anisole solvate) of Ibrutinib
The present inventors has repeated the above process and found the following disadvantages:                In most of the patent literature, Mitsunobu coupling was performed using costly reagents like Diazo Isopropyl Dicarboxyalate (DIAD) and Triphenyl Phosphine (TPP), which is not much efficient scalable process. Further, TPP is a Genotoxic compound, which requires several purification steps to yield highly pure Ibrutinib, which meets the requirements of ICH guidelines.        In most of the patent literature Acryloyl chloride was used, which was easily polymerizable and not much stable compound leading to formation of majority impurities.        Unwanted reactions are observed during the formation of Ibrutinib, due to the involvement time lagging process.        Incomplete reactions were observed with excessive impurity formation due to incomplete conversion.        
In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of Ibrutinib, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.